Specific mechanisms of how the reactive microenvironment affects prostate cancer progression are unknown. Previous studies from our group have shown that the reactive microenvironment has properties and gene expression similar to wound repair biology. These include changes in stromal cell phenotype, altered neurogenesis and the involvement of specific T regulatory cells. We have also shown that reactive stroma is tumor promoting. These studies have shown that carcinoma cells and nerves exhibit reciprocal interactions leading to elevated carcinoma proliferation and induced neurogenesis. In addition, the involvement of gamma-sigma T regulatory cells may play an important role in tumor progression. The concurrent recruitment of myofibroblasts to PIN and carcinoma foci implicates a coordinated host response in these biologies that promotes tumorigenesis. Importantly, our group has shown that specific biomarkers of this reactive microenvironment are predictive of recurrence of human prostate cancer. The integrated biologies of this response and specific mechanisms are not yet understood at a level where more effective prognostics or novel therapeutics can be developed. Accordingly, the overall objectives of this project are to understand how reactive stroma, neurogenesis, and immunity responses in prostate cancer microenvironment function and interact mechanistically during the initiation and progression of early, organ confined disease. The endpoint of this study is to understand the key components, regulators, and mechanisms with a specific focus on early prostate cancer. We have assembled a team of experts who will focus their efforts on understanding three interrelated biologies in the tumor microenvironment. We propose a Program composed of an Expression Analysis and Pathology Core and three interrelated Projects. Project 1 will address the co-evolution, origin, and specific regulators of reactive stromal cells. Project .2 will address the role of axonogenesis and neurogenesis in regulating early cancer. Project 3 will focus on the role of gamma-sigma T regulatory cells and signaling through Toll-like receptors in prostate cancer progression. Together, these Projects and Core will provide fundamental data regarding the temporal and spatial composition, gene expression profiling, and potential regulators of the microenvironment in human tissues and mouse models. This group of Investigators has worked together for several years and has planned these studies around their pre-established collaborations. The overall goal of this Program is to provide novel pre-clinical data, from which more effective biomarkers and therapeutics can be developed that target the microenvironment of early prostate cancer.